2-Substituted-phenyl-1,3-perhydrothiazine-4-one

ABSTRACT

Compounds of 2-substituted-phenyl-1,3-perhydrothiazine-4-one having the formula (I) ##STR1## wherein R represents a lower alkyl group of 1 to 3 carbon atoms and n denotes an integer of 1 to 3 possess anti-peptic ulcer activity.

BACKGROUND AND SUMMARY OF THE INVENTION

The present invention concerns novel compounds, their preparation andtheir use as anti-peptic ulcer medicine. More particularly, the presentinvention concerns novel compounds of2-substituted-phenyl-1,3-perhydrothiazine-4-one which are useful asanti-peptic ulcer medicines.

Originally, the peptic ulcer is the collapsed weakened parts of thegastric or enteric mucosa by the action of aggressive factors such ashydrochloric acid and pepsin in the gastric juice. The mild cases ofpeptic ulcer are curable after 3 to 4 month of hospitalization andtreatment, however, the serious cases are accompanied by hemorrhage andperforation of the organ and become chronic.

As an etiological cause of peptic ulcer, the abnormalities in theautonomic nerve system and in the mucosal blood flow due to physicaland/or mental stress has been considered, however, it is practicallyimpossible to interpret the etiology of peptic ulcer unitarily becausethe viscera themselves are subjected to complicated control by thenerves and hormones.

Hitherto, as an anti-peptic ulcer medicine, sodium hydrogen carbonate,alminum salts and magnesium salts have been used for a long time in themeaning of neutralizing the above-mentioned acid as the aggressivefactor. However, these medicines only temporarily neutralize the acid toalleviate the pain and do not accelerate the substantial cure of theulcer.

Recently, many kinds of anti-ulcer medicines have been developed basedon the presumable causes of ulcer, including the medicines suppressingautonomic nerve, that is, so-called anti-cholinergic agents, the agentsrepairing the damaged tissues and the agents improving the blood flow.However, the present situation is that none of them can be said to besatisfactory in view of their effectiveness or their side effects.

For instance, carbenoxolone which has been commercialized as ananti-peptic ulcer medicine has been broadly used because of itsexcellent accelerating effect on the ulcer-curing, however, it has analdosterone-like side effects to cause hypertension and weakening ofmuscular function when taking continuously. In addition, theabove-mentioned anti-cholinergic agent shows severe side effects such asmydriasis and thirst due to the blocking of the parasympathetic nerve,and it has been reported their effects of accelerating the ulcer-curingis low.

Since it generally takes a long time period for curing the peptic ulcer,the period of administration of an anti-peptic ulcer medicine extends to100 to 150 days on the average. And accordingly, it is required that theanti-peptic ulcer medicine is highly safe as well as highly effective inulcer-curing.

An object of the present invention provides an anti-peptic ulcermedicine excellent in anti-peptic ulcer action and pharmacologicallysafe.

Another object of the present invention provides a compound useful as ananti-peptic ulcer medicine.

DETAILED EXPLANATION OF THE INVENTION

The novel compounds according to the present invention are2-substituted-phenyl-1,3-perhydrothiazine-4-one represented by thefollowing formula: ##STR2## wherein R is a lower alkyl group of 1 to 3carbon atoms, and n is an integer of 1 to 3.

2-Substituted-phenyl-1,3-perhydrothiazine-4-one represented by theabove-mentioned formula (I) have excellent anti-peptic ulcer action andare pharmacologically safe compounds.

2-Substituted-phenyl-1,3-perhydrothiazine-4-one according to the presentinvention (hereinafter referred to as the present compounds) include thefollowing compounds:

2-(3,4,5-trimethoxyphenyl)-1,3-perhydrothiazine-4-one,

2-(2,3,4-trimethoxyphenyl)-1,3-perhydrothiazine-4-one,

2-(2,3-dimethoxyphenyl)-1,3-perhydrothiazine-4-one,

2-(2,4-dimethoxyphenyl)-1,3-perhydrothiazine-4-one,

2-(2,5-dimethoxyphenyl)-1,3-perhydrothiazine-4-one,

2-(2,6-dimethoxyphenyl)-1,3-perhydrothiazine-4-one,

2-(3,4-dimethoxyphenyl)-1,3-perhydrothiazine-4-one,

2-(3,5-dimethoxyphenyl)-1,3-perhydrothiazine-4-one,

2-(2-methoxyphenyl)-1,3-perhydrothiazine-4-one,

2-(3-methoxyphenyl)-1,3-perhydrothiazine-4-one and

2-(4-methoxyphenyl)-1,3-perhydrothiazine-4-one.

The melting points, appearances and elementary analytical compositionsof the present compounds are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________                                                   Elementary analytical                                                         com-                           Compound                         Melting point position (%)                   number                                                                              Name of compound                                                                          Structural formula                                                                           (°C.)                                                                         Appearance                                                                           C   H   N   S                  __________________________________________________________________________    1     2-(3,4,5-trimethoxy- phenyl)-1,3-perhydro- thiazine-4-one                                  ##STR3##      181-182                                                                              colourless acicular                                                                  55.09 (55.11)                                                                     6.07 (6.05)                                                                       4.92 (4.94)                                                                       11.29 (11.32)      2     2-(3,4-dimethoxyphenyl)- 1,3-perhydrothiazine-4- one                                       ##STR4##      166-167                                                                              colourless minute acicular                                                           56.92 (56.90)                                                                     5.96 (5.97)                                                                       5.53 (5.53)                                                                       12.69 (12.66)      3     2-(2-methoxyphenyl)-1,3- perhydrothiazine-4-one                                            ##STR5##      201.5-203                                                                            colourless prism                                                                     59.14 (59.17)                                                                     5.90 (5.87)                                                                       6.25 (6.27)                                                                       14.39 (14.36)      4     2-(4-methoxyphenyl)-1,3- perhydrothiazine-4-one                                            ##STR6##      185.5-186.5                                                                          colourless acicular                                                                  59.19 (59.17)                                                                     5.86 (5.87)                                                                       6.26 (6.27)                                                                       14.37 (14.36)      __________________________________________________________________________     Note:                                                                         The parenthesized values in Elementary Analytical Composition represent       the theoretical values based on the molecular formula of each compound.  

The present compound may be produced by either of the following twomethods (1) and (2):

(1) A process which comprises reacting an aldehyde represented by theformula (II): ##STR7## wherein R represents a lower alkyl group of 1 to3 carbon atoms and n is an integer of 1 to 3, with 3-mercaptopropionicacid or an ester thereof and an ammonium compound in an inert solventsuch as benzene, toluene and xylene. Preferably an equimolar or a slightexcess of the 3-mercaptopropionic acid or ester thereof is used. Theammonium compound, preferably ammonium carbonate, is used in an amountof a slight excess as ammonia. The reaction can be carried out at atemperature of 50° to 150° C., usually at the boiling point of thesolvent for 1 to 10 hours.

The method (1) can be summarized as follows: ##STR8## wherein Rrepresents a lower alkyl group with 1 to 3 carbon atoms, R¹ represents ahydroxyl group or an alkoxy group with 1 to 2 carbon atoms, and ndenotes an integer of 1 to 3.

(2) A process which comprises reacting an aldehyde represented by theformula (II) with 3-mercaptopropionic acidamide in an inert solvent suchas benzene, toluene and xylene. Preferably an equimolar or slight excessof 3-mercaptopropionic acidamide is used. The reaction can be carriedout at a temperature of 50° to 150° C., usually at the boiling point ofthe solvent, for 1 to 3 hours.

No matter which method may be adopted, on cooling the reaction mixtureafter the reaction is over, the object product separates out ascrystals, and accordingly, the crystals are collected by filtration andusing a solvent ordinarily used for recrystallization such as benzene,methanol or ethanol, they are purified by recrystallization.

In the next place, the pharmacological and toxicological properties ofthe present compounds are explained.

The important problem in the development of anti-peptic ulcer medicineis the screening system thereof. Hitherto, the evaluation of anti-ulcermedicines has been frequently carried out based on their prophylacticeffect against the acute ulcer such as ulcer due to pyloric ligation,aspirin or indomethacin. However, to what extent the result ofevaluation by these ulcer models reflect the curing effect on humanulcer has not been fully elucidated.

The inventors of the present invention, taking into account of thesesituations, added to the above-mentioned method of evaluation the effectof accelerating the cure of the peptic ulcer by orally administering thepresent compound and a commercialized anti-peptic ulcer medicine,respectively to rats to which duodenal peptic ulcer due to acetic acid(refer to Okabe, 1971) considered to be most closely resembling to humanpeptic ulcer has been artificially formed.

Anti-peptic ulcer effect of the present compound (1) Effect on pepticulcer due to pyloric ligation

Six groups (10 animals per group) of male rats weighing 180 to 200 gwere subjected to ligation of their pyloruses under ether-anesthesiaafter fasting for 48 hours according to the method of Shay et al. (referto Gastroenterology, 5, page 43 (1945)).

Just after subjecting to ligation, each of the present compoundsuspended in an aqueous physiological saline solution wasintraperitoneally administered to each rat, the control being injectedwith an aqueous physiological saline solution. Then, after 15 hours offasting without taking water, the rats were sacrificed with ether andtheir stomachs were removed to examine under a microscope for anatomy.The length and width of the thus-formed ulcer in the stomach weredetermined and expressed by the product (mm²), and the total sum of theproducts was represented as the ulcer coefficient. The results are shownin Table 2.

                  TABLE 2                                                         ______________________________________                                                              Ulcer                                                   Compound   Dose rate  coefficient                                                                              Rate of                                      number     (mg/kg)    (mm.sup.2) suppression.sup.(1)                          ______________________________________                                        1          100        9.3        74.9                                         2          100        1.9        94.3                                         3          100        2.4        93.5                                         4          100        2.0        94.5                                         Positive control.sup.(2)                                                                 100        32.5       12.2                                         Control    --         37.0       0                                            ______________________________________                                         Notes                                                                         .sup.(1) Rate of suppression of ulcer                                         ##STR9##                                                                      .sup.(2) Positive control: Gefarnate =                                        3,7dimethyl-2,6-octadienyl-5,9,13-trimethyl-4,8,12-tetradecatrienoate    

(2) Effect on peptic ulcer due to acetic acid

Following the method of Okabe et al (refer to Amer. J. Dig. Dis., 16,(1977)), 6 groups (15 animals per group) of male rats weighing 240 to260 g were subjected to laparotomy under ether anesthesia in which ametal circular frame was placed on the serosa at a distance of 5 to 7 mmfrom the duodenal pylorus, 0.06 ml of glacial acetic acid was pouredinto the frame. After 30 seconds, the liquid containing the acetic acidwas removed and then the frame was removed. The test compound suspendedin an aqueous 0.5% solution of carboxymethylcellulose was orallyadministered to the rat 3 times a day from the third day of theoperation for consecutive 10 days. To the control group, only thesolution of carboxymethylcellulose was administered. After theadministration was over, the rats were sacrificed with ether, and theirduodenum was removed to observe under a microscope for anatomy. Thelength and width of the thus-formed ulcer were measured and theirproduct (expressed with mm²) was recorded as the ulcer coefficient. Theresults are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                             Ulcer                                                    Compound   Dose rate coefficient                                                                             Rate of suppression                            number     (mg/kg)   (mm.sup.2)                                                                              of ulcer (%)                                   ______________________________________                                        1          100       2.5       67.1                                           2          100       2.0       73.6                                           3          100       1.5       80.2                                           4          100       1.3       82.8                                           Positive control.sup.(1)                                                                 100       6.1       20.0                                           Control    --        7.6       0                                              ______________________________________                                         Note:                                                                         .sup.(1) Positive control: gefarnate (refer to the footnote of Table 2)  

By the way, the above-mentioned experimental model has been highlyevaluated internationally because the thus-formed ulcer is scarcelycurable in nature and the histopathological change of the ulcer lesionclosely resembles to that of human chronic ulcer as compared to themethod of cautery-ulcer (refer to Skoryna, 1958) and the method ofcrumping-cortisone (refer to Umehara, 1965).

(3) On the evaluation by the hitherto broadly utilized effective methodsfor screening anti-peptic ulcer medicines such as those of stress-ulcer,aspirin-ulcer and indomethacin-ulcer, the present compounds showedsuperior effects to the effects of commercialized anti-peptic ulcermedicines.

Toxicological properties of the present compound

(1) Acute toxicity test

Experimental animal:

Female ICR-mice of body weight of 20 to 24 g, 5 weeks after birth wereused.

Method of rearing:

Eight animal per group were kept in a transparent polycage at roomtemperature of 23°±1° C., and RH of 60 to 70%.

Administration of the present compound:

After minutely pulverizing each one of the present compounds, thepulverized compound was suspended in an aqueous 5% sodiumcarboxymethylcellulose solution containing 20% of Tween-80. The aqueoussuspension was forcibly orally administered by a metal stomach tube, thedose rate having been adjusted by changing the concentration of thepresent compound in the aqueous suspension.

General symptoms due to the present compound:

In cases of administering at higher dose rate, the movement of the ratsbecame inactive, however, after 2 to 3 hours, they became normal. Insome mortal cases, the rat's spontaneous movement was lowered with thereduction of general tension and the rats died as they were.

Calculation of LD₅₀ :

The rats' mortality was observed for a week after the administration,and LD₅₀ was calculated from the mortality by the Litchfield-Wilcoxon'sformula. The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Compound                                                                      number       LD.sub.50 (p.o.) (mg/kg)                                         ______________________________________                                        1             5400                                                            2            more than 8000                                                   3            more than 8000                                                   4            more than 8000                                                   ______________________________________                                    

In addition, according to the results of acute toxicity test using ratsand mice as experimental animals, LD₅₀ i.v. was larger than 1.5 g/kg.

(2) Sub-acute toxicity test

Experimental animal:

Both sexes of Sprague-Dowley rats of 110 to 150 g of body weight after 5months of their birth were used.

Method of rearing:

Each five males and five females were respectively kept in a metalwire-net cage at room temperature of 22° to 24° C. and RH of 60 to 70%for 3 months, each experimental group consisting of 10 males or 10females.

Administration of the present compound:

Compound No. 2 of the present compounds,2-(3,4-dimethoxyphenyl)-1,3-perhydrothiazine-4-one, was minutelypulverized and mixed with the powdery diet for rat at a concentration of0.4% by weight. The thus prepared diet was taken ad lib. The mean intakeof the present compound was 400 mg/kg/day.

Examination:

The diet intake and the body weight of each rat were measured everyother day and once a week, respectively. The urinalysis for glucose,protein, pH, and occult blood was carried out once a month. Blood samplewas examined after ending the rearing, and after sacrificing all theanimals, they were autopsied to examine the presence of abnormalities.Their organs were fixed with formaldehyde and imbedded in paraffin toprepare sliced specimens of tissues stained with hematoxylineosine formicroscopic observation.

Results:

(a) Diet intake was normal without significant difference betweenexperimental groups and control group.

(b) Body weight gain was normal without significant difference betweenexperimental groups and control group.

(c) Mortality, (d) urinalysis, (c) hematological examination, and (f)findings on autopsy and histological examination were all normal withoutany significant difference between experimental groups and controlgroup.

Further, in the sub-acute toxicity test using mice as experimentalanimals, abnormal findings attributable to the present compound couldnever be obtained.

As is seen above, the present compound is highly safe for administrationand accordingly, it can be used as an anti-peptic ulcer medicine inhuman cases.

In addition to its excellent pharmacological effects and toxicologicalproperties, every compound of the present invention is colourless andcrystalline, and almost of them are tasteless or are only slightlybitter. Furthermore, since they are extremely stable without any changeafter storing at room temperature in an open state, their adaptabilityas an anti-peptic ulcer medicine can be said remarkably high.

A pharmaceutical composition according to the present invention isuseful for treatment of peptic ulcer, and comprises a therapeuticallyeffective amount of the present compound together with apharmaceutically acceptable carrier. The pharmaceutical composition isin unit dosage form, e.g. as tablets, sugar-coated tablets, pills,capsules, powders, granules, troches, liquids, suppositories,injections, etc.

As the carrier, lactose, sucrose, sorbitol, mannitol, potato-starch,corn-starch, amylopectin, various kinds of starch, derivatives ofcellulose (for instance carboxymethylcellulose and methylcellulose),gelatin, magnesium stearate, calcium stearate, polyvinyl alcohol,polyethylene glycol waxes, gum arabic, talk, titanium dioxide, vegetableoil such as olive oil, peanut oil and sesame oil, paraffin oil, neutralfatty bases, ethanol, aqueous physiological saline solutions, sterilizedwater, glycerol, colouring agents, flavorings, thickening agents,stabilizers, isotonic agents and buffering agent can be exemplified.

The content of the one of the present compounds in the above-mentionedpharmaceutical composition is 0.1 to 90% by weight, preferably 1 to 60%by weight of the preparation.

The clinical daily dose of the present compound is 60 to 6000 mg/60 kgof body weight, preferably, 600 to 3000 mg/60 kg body weight. The routeof administration may oral or injectional, and it is preferablyadministered orally in the case of long term administration.

The followings are the more detailed explanation of the presentinvention while referring to examples, however, it should be understoodthat the scope of the present invention is never restricted to Examplesshown as follows:

SYNTHETIC EXAMPLES OF THE PRESENT COMPOUNDS EXAMPLE 1 Synthesis of2-(3,4,5-trimethoxyphenyl)-1,3-perhydrothiazine-4-one

A mixture of 19.6 g of 3,4,5-trimethoxybenzaldehyde, 10.6 g of3-mercaptopropionic acid and 6 g of ammonium carbonate in 250 ml ofbenzene was refluxed for 5 hours at 80° C. in a flask provided with aDean-Stark apparatus and the thus distilled water was removed. Thecrystals which separated out from the reaction mixture after reactionwas over and on cooling the reaction mixture, were collected byfiltration and recrystallized from benzene to give 21.8 g of colourlessaciculates melting at 181° to 182° C. in a yield of 77%.

EXAMPLE 2 Synthesis of2-(3,4-dimethoxyphenyl)-1,3-perhydrothiazine-4-one

A mixture of 16.6 g of 2,4-dimethoxybenzaldehyde, 10.6 g of3-mercaptopropionic acid and 6 g of ammonium carbonate in 250 ml ofbenzene was refluxed for 3 hours in a reaction vessel provided with aDean-Stark apparatus at 80° C. while removing the distilled water. Thecrystals which separated out after cooling the reaction mixture werecollected by filtration and recrystallized from hot benzene to obtainthe object, colourless minute acicular crystals melting at 166° to 167°C. in an amount of 22 g corresponding to a yield of 87%.

EXAMPLE 3 Synthesis of 2-(2-methoxyphenyl)-1,3-perhydrothiazine-4-one

A mixture of 13.6 g of o-anisaldehyde, 10.6 g of 3-mercaptopropionicacid and 6 g of ammonium carbonate in 250 ml of toluene was refluxed at110° C. for 2 hours in a flask provided with a Dean-Stark apparatuswhile removing the distilled water. The crystals which separated outafter leaving the reaction mixture for a night were collected byfiltering and recrystallized from hot dimethylformamide to obtain theobject, colourless prisms melting at 201.5° to 203° C. in an amount of18.7 g corresponding to a yield of 84%.

EXAMPLE 4 Synthesis of 2-(4-methoxyphenyl)-1,3-perhydrothiazine-4-one

A mixture of 13.6 g of p-anisaldehyde and 10.5 g of 3-mercaptopropionicacid amide in 150 ml of benzene was heated at 80° C. for 2 hours. Thecrystals which separated out after leaving the reaction mixture for anight were collected by filtration and recrystallized from hot benzeneto obtain colourless minute aciculates melting at 185.5° to 186.5° C. inan amount of 21 g corresponding to a yield of 94%.

MANUFACTURE OF THE PHARMACEUTICAL PREPARATIONS EXAMPLE 5 Manufacture ofthe granular preparation for oral administration

Two hundred grams of 2-(3,4-dimethoxyphenyl)-1,3-perhydrothiazine-4-onewas minutely pulverized and 800 g of corn-starch was admixed with thepulverized compound. After stirring the mixture well, 80 ml of anaqueous solution containing 3 g of sodium carboxymethylcellulosedissolved therein was added to the mixture, and after kneading the wholemixture, it was subjected to an extruding pelletizer to be granularshape. The shaped mixture was dried at a temperature of 60° to 80° C.and screened to obtain the granular preparation for oral administration.

What is claimed is:
 1. A process for preparing a compound of2-substituted phenyl-1-1, 3-perhydrothiazine-4-one represented by theformula ##STR10## wherein R represents a lower alkyl group of 1 to 3carbon atoms and n denotes in integer of 1 to 3, which comprisesreacting an aldehyde represented by the formula ##STR11## wherein R andn are as defined above, with 3-mercaptopropionic acid amide in an inertsolvent.
 2. A process according to claim 1, wherein the reaction iscarried out at a temperature of 50° to 150° C.
 3. A pharmaceuticalanti-ulcer composition in a dosage unit form, which comprises a dosageeffective for treatment of peptic ulcer of a 2-substitutedphenyl-1,3-perhydrothiazine-4-one represented by the formula ##STR12##wherein R represents a lower alkyl group of 1 to 3 carbon atoms and ndenotes an integer of 1 to 3, and a pharmaceutically acceptable carrier.4. A method for treatment of peptic ulcer which comprises administeringto an animal suffering from peptic ulcer an amount effective fortreatment of peptic ulcer of a 2-substitutedphenyl-1,3-perhydrothiazine-4-one represented by the formula ##STR13##wherein R represents a lower alkyl group of 1 to 3 carbon atoms and ndenotes an integer of 1 to 3.